Bioterrorism is no longer a threat in the United States, but a reality. In 2001, the spread of anthrax spores through the U.S. mail illustrated that deadly agents can be acquired and spread using relatively unsophisticated means. It also highlighted our vulnerability to such attacks and the urgency for preparedness. Vaccine-induced protective immunity to potential bioterror weapons could be one of the most effective biodefense strategies. Most of the biodefense vaccines available have been tailored for military personnel (healthy adults). The civilian population in need of protection, however, includes people of all ages and physical conditions (newborns, infants, immunocompromised and the elderly), who are at greater risk and could become the enemy's sinister targets to inflict more casualties. Clearly, there is an urgent need for safe and effective vaccines for these highly vulnerable groups. We propose to evaluate protective efficacy of a new generation of biodefense vaccines based on attenuated Salmonella as a live vector to mucosally deliver protective antigens from Yersinia pestis and Bacillus anthracis. Our first goal is to determine whether these Salmonella biodefense vaccines are well tolerated and induce long-lasting protective immunity using a neonatal mouse model of immunogenicity that closely resembles the responses in humans. Based on preliminary data, we hypothesize that 1) Salmonella live vectors will be highly immunogenic in newborn mice; and 2) antibody and cell-mediated immunity will be induced despite the presence of maternal antibodies. We also aim to explore the mechanisms involved in the induction of neonatal adaptive immunity to Salmonella and encoded foreign antigens. Although neonatal responses to vaccines are usually feeble and Th2 biased, our preliminary data suggest that Salmonella-based biodefense vaccines can induce potent (adult-like) and balanced Th1/Th2- type responses in newborns despite the presence of maternal antibodies. We hypothesize that this is linked to the the capacity of the bacteria to induce neonatal dendritic cell maturation and T cell activation. This research will be highly relevent to public health as it will enable us to identify biodefense vaccines that can be safe and protect children and infants against bioterror weapons. It will also provide knowledge to better understand the mechanisms mediating neonatal-infant immunity to develop more effectivevaccines to prevent diseases early in life.